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Review
. 2016 Sep 15:1647:30-42.
doi: 10.1016/j.brainres.2016.04.003. Epub 2016 Apr 6.

RAN translation-What makes it run?

Katelyn M Green  1 , Alexander E Linsalata  1 , Peter K Todd  2
Affiliations
Review

RAN translation-What makes it run?

Katelyn M Green et al. Brain Res. .

Abstract

Nucleotide-repeat expansions underlie a heterogeneous group of neurodegenerative and neuromuscular disorders for which there are currently no effective therapies. Recently, it was discovered that such repetitive RNA motifs can support translation initiation in the absence of an AUG start codon across a wide variety of sequence contexts, and that the products of these atypical translation initiation events contribute to neuronal toxicity. This review examines what we currently know and do not know about repeat associated non-AUG (RAN) translation in the context of established canonical and non-canonical mechanisms of translation initiation. We highlight recent findings related to RAN translation in three repeat expansion disorders: CGG repeats in fragile X-associated tremor ataxia syndrome (FXTAS), GGGGCC repeats in C9orf72 associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and CAG repeats in Huntington disease. These studies suggest that mechanistic differences may exist for RAN translation dependent on repeat type, repeat reading frame, and the surrounding sequence context, but that for at least some repeats, RAN translation retains a dependence on some of the canonical translational initiation machinery. This article is part of a Special Issue entitled SI:RNA Metabolism in Disease.

Keywords: Amyotrophic lateral sclerosis; C9orf72; Fragile X-associated tremor ataxia syndrome; Frontotemporal dementia; Huntington disease; Translation initiation.

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Figures

Figure 1
Figure 1. Canonical scanning model of translation initiation
Step 1 - The eIF4F complex, composed of eIF4E, eIF4G, eIF4A, binds to the 5’m7G cap with eIF4B and/or eIF4H. PABP associates with eIF4G to circularize the mRNA. Step 2 - The eIF4F complex recruits the 43S Pre-initiation complex (PIC), composed of the 40S ribosomal subunit, eIF1, eIF1A, eIF3, eIF5, and the ternary complex, consisting of the initiator methionine-tRNA, eIF2, and GTP. Step 3-4 - The PIC and components of the eIF4F complex scan through the 5’ UTR in the 5’ to 3’ direction until encountering an AUG start codon in a good Kozak context. Step 5–eIF1 dissociates from the PIC, and eIF2 hydrolyzes GTP with the assistance of eIF5, committing the 40S ribosome to translation initiation at the present AUG codon. Step 6 - eIF5B-GTP promotes association of the 60S subunit and displacement of most eIFs. Step 7–eIF5B hydrolyzes its bound GTP and dissociates with eIF1A, establishing the elongation-competent 80S ribosome. eIF = eukaryotic initiation factor, m7G = 7 methylguanosine, PABP = poly-adenosine binding protein, PIC = preinitiation complex.
Figure 2
Figure 2. Canonical and alternative mechanisms of translation initiation
A) In canonical translation initiation, the 43S PIC with a full complement of eIFs binds to the 5’m7G cap, then linearly scans through the 5’ UTR until reaching an AUG start codon in good Kozak context. B) The poliovirus IRES uses complex RNA secondary structure to recruit nearly all eIFs to an internal site within the transcript, bypassing the eIF4E-m7G interaction. The 43S PIC is subsequently recruited, and then scans 5’ to 3’ to the start codon. C) The CrPV IRES requires and recruits only the 40S and 60S ribosomal subunits and an alanine-conjugated tRNA, initiating translation at a CCU codon in the absence of any eIFs. D) Translation of Histone 4 mRNA begins with tethering of eIF4F and the 43S PIC to internal secondary structures. The 40S subunit is then transferred to the AUG start codon upstream.
Figure 3
Figure 3
Production of RAN-translated proteins across different sequence contexts. A) When located in the 5’ UTR, as in FMR1, expanded GC-rich repeats trigger initiation of RAN translation upstream of the canonical AUG start codon, leading to the production of FMRpolyG and FMRpolyA. B) When located in an intron, as in C9orf72, it is unclear what RNA species is the substrate for RAN translation: a spliced lariat, an aberrantly spliced transcript in which the intron is retained, or a 3’ truncated RNA resulting from stalled transcription. The relevant RNA species produces polyGA, polyGR, and polyGP RAN-translation products. C) When located within an ORF, as in HTT, canonical translation still initiates at the AUG codon upstream of the repeats. However, expression of polyserine (polyS) and polyalanine (polyA) proteins occurs by a combination of RAN-translation through the repeats and frameshifting out of the native (polyglutamine; polyQ) frame. D) Repeats located in antisense transcripts, as in C9orf72 and asHTT, are also substrates for RAN translation, further expanding the number of dipeptide or homopolymeric RAN proteins. The post-transcriptional modification state of these transcripts (e.g. mRNA capping and polyadenylation) are unknown.
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References

    1. Al-Sarraj S, King A, Troakes C, Smith B, Maekawa S, Bodi I, et al. p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS. Acta Neuropathol. 2011;122(6):691–702. - PubMed
    1. Allingham-Hawkins DJ, Babul-Hirji R, Chitayat D, Holden JJ, Yang KT, Lee C, et al. Fragile X premutation is a significant risk factor for premature ovarian failure: the International Collaborative POF in Fragile X study--preliminary data. Am J Med Genet. 1999;83(4):322–5. - PMC - PubMed
    1. Anderson DM, Anderson KM, Chang CL, Makarewich CA, Nelson BR, McAnally JR, et al. A micropeptide encoded by a putative long noncoding RNA regulates muscle performance. Cell. 2015;160(4):595–606. - PMC - PubMed
    1. Ash PE, Bieniek KF, Gendron TF, Caulfield T, Lin WL, Dejesus-Hernandez M, et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron. 2013;77(4):639–46. - PMC - PubMed
    1. Bañez-Coronel M, Ayhan F, Tarabochia AD, Zu T, Perez BA, Tusi SK, et al. RAN Translation in Huntington Disease. Neuron. 2015;88(4):667–77. - PMC - PubMed

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